Glycodiversification for the Synthesis of Neomycin ... - ACS Publications

Chapter 17

Glycodiversification for the Synthesis of Neomycin and Kanamycin Class Aminoglycoside Antibiotics

Downloaded by CORNELL UNIV on October 24, 2016 | http://pubs.acs.org Publication Date: March 13, 2007 | doi: 10.1021/bk-2007-0960.ch017

Jinhua Wang and Cheng-Wei Tom Chang* Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, UT 84322-0300

Aminoglycosides are an important resource against infectious diseases. However, the prevalence of aminoglycoside resistant bacteria has limited their use and resulted in the need for novel aminoglycosides. Our group has synthesized two libraries of aminoglycosides: pyranmycin and kanamycin analogs, utilizing the glycodiversification concept. Several of them show promising activity against both susceptible and resistant strains of E. coli. The structure activity relationship of these compounds further provides information for the future designs of aminoglycoside.

Introduction The emergence of drug resistant microorganisms represents stringent public health problems. (7-5) The annual cost of treating antibiotic resistant infections in the United States alone has been estimated to be as high as $30 billion. (6, 7) In responding to the call for new drug development, aminoglycosides, which have the advantage of high and broad-spectrum activity, are one of the ideal solutions against infectious diseases. Aminoglycosides are a group of structurally diverse antibiotics consisting of various numbers of normal and unusual sugars. Neomycin and kanamycin are two of the most studied aminoglycoside antibiotics (Figure 1). Neomycin belongs to a group of aminoglycosides containing a 4,5-disubstituted 2deoxystreptamine core (ring II), while kanamycin contains a 4,6-disubstituted 2deoxystreptamine core. (I

E. coli (TGI) (pTZ19U-3) 0.5 Inactive 4 Inactive

d

a


b c

d

against the problem of drug resistance, numerous chemical modifications of kanamycin have been reported with the goal of reviving its activity toward resistant bacteria. (27, 35-57) Except for a few publications, (38, 39) the majority of derivatives have been directed into the modification on kanamycin scaffold, which limits the options for structural modifications.

First Generation of Kanamycin B Analogs Similar to the construction of pyranmycin, a library synthesis of novel kanamycin B analogues has been developed. (40) The neamine acceptor, 22, undergoes regiospecific glycosylation at 0-6 position, resulting in the desired 4,6-disubstituted 2-deoxystreptamine motif (Scheme 6). (39, 41, 42) The glycosylation donors have benzyl or azido groups at the C-2 position, which favor the formation of an a-glycosidic bond under the influence of anomeric and solvent effects. (43) The kanamycin analogues were tested against E. coli (ATCC 25922), and S. aureus (ATCC 25923) using kanamycin B as the control, revealing a lead JL027.

Modification at 0-4" Position Combined SAR information from first generation of kanamycin B analogs allows us to identify 4"-OH of ring III as the optimal site for further modification. Since kanamycin exerts its antibacterial activity by binding toward rRNA, a highly negatively-charged molecule due to the phosphate diester backbone, it is our expectation that by introducing more positively-charged side chain at the 0-4" position, an increase in the antibacterial activity can be obtained.

Demchenko; Frontiers in Modern Carbohydrate Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 2007.


320



2

OH OH OH OH OH OH NH

JL028 JL029 JL030 JL031 JL032 JL033 JL034

2

%

>-

u

2

2

2

N

y - H OH OH yO> A^NH

V —

NH

2 3

-0(CH ) NH OH

2

Figure 5. Structures ofKanamycin Analogs with Extended Arm

HN

Ri

Compound


25: 1

35: 1

only a

only a

20:1

only a

30: 1

Glycodiversification for the Synthesis of Neomycin ... - ACS Publications

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